Therapeutic vascular occlusions (embolizations) are techniques used to treat certain pathological conditions in situ. Therapeutic embolization is practiced generally using a catheter, under imagery control, to position particulate embolization agents in the circulatory system, such as the vessels of various processes: tumors, vascular malformations, and hemorrhagic processes. Notably, vascular occlusion can suppress pain or pressure sensations, limit blood loss (e.g., during a surgical intervention following embolization), or even prompt necrosis. In the case of vascular malformations, embolization can normalize blood flow to normal tissue, aid in surgery, and limit the risk of hemorrhage. In hemorrhagic processes, vascular occlusion produces a reduction of blood flow, which promotes cicatrization of arterial openings. U.S. Pat. No. 5,635,215 discloses the use of hydrophilic acrylic copolymer microspheres coated with a cell adhesion promoter for therapeutic embolization.
Uterine Artery Embolization (UAE) is the process of occluding the vascular blood supply to uterine fibroids to reduce fibroid size and alleviate associated symptoms, including bleeding, pain, and disfigurement. Fibroids are benign tumors of smooth muscle. They are also called leiomyomas or myomas. Fibroids may arise in different parts of the uterus. They are named by their position within the uterus; submucosal, intramural, and subserosal. Some fibroids grow on a stalk and these are called pedunculated. Abnormal bleeding can be caused by submucosal or intramural fibroids. Intramural and subserosal fibroids can cause pelvic pain, back pain, and generalized pressure sensations. Fibroids often fail to respond to medical therapies, causing either myomectomy (surgical removal of the fibroids) or hysterectomy to be an ultimate treatment.
In recent years, there has been considerable research aimed at developing less invasive alternatives to surgical treatments of fibroids. One such alternative is uterine fibroid embolization.
PCT/GB98/02621 discloses a bio-compatible, embolizing agent comprising polymer particle such as polyvinyl alcohol, containing a contrast enhancing material. The contrast enhancing materials can be located on the surface or in the pores of, or within micro-balloons formed from, the polymer particles. Consequently, the polymer particles retain a contrast enhancing effect in vivo for a prolonged period of at least seven days, or preferably at least fourteen days, and particularly preferably until the polymer particles biodegrade.
PCT/US99/04398 discloses a method for gynecological endovascular embolization with a fluid embolic composition that halicize forms a coherent solid mass. The embolization agent is a composition of biocompatible polymers and a radiopaque material. In some applications where a water soluble radiopaque material is used, the composition does not contain any particles. The particle size is no more than 100 micrometers and preferably less than 10 micrometers.
U.S. Pat. No. 4,999,188 (Solodovnik et al.) discloses a composition for embolization of blood vessels, in which agglomeration of particles is decreased as the composition is introduced. The proposed composition can additionally comprise a medicinal or radiopaque substance or a mixture of these in an amount of about 0.005 to about 8% by weight in relation to the total weight of the initial ingredients. The particles of the embolizing material may include particles of a polymer material moderately swelling in water, particles of glass or metal or a mixture thereof Suitable polymeric particles include acetylcellulose, acetylphtalylcellulose, polyvinylacetate, copolymers of vinylpyrrolidone and methylmethacrylate.
U.S. Pat. No. 5,202,352 (Okada et al.) discloses an intravascular embolizing agent containing an angiogenesis-inhibiting substance and an intravascular embolizing substance. The agent, with the administration of a relatively small dosage amount, enhances the anti-tumor effect of the angiogenesis-inhibiting substances. The addition of small doses of angiogenesis inhibiting substances also enhances the anti-tumor effect of intravascular embolizing agents.
U.S. Pat. No. 5,236,410 (Granov et al.) discloses a method for tumor treatment which involves first catheterization of the vessel that supplies a tumor of interest. A suspension of a magnetically hard ferromagnetic substance in an oil solution of oil-soluble antitumor agent is then injected through the catheter under fluoroscopic control and, at the same time, local magnetic field is applied onto the tumor-bearing area. After 1-3 days, the tumor is subjected to oscillating power field selected from ultrahigh radio frequency electromagnetic field and the field of ultrasonic contraction waves until the temperature of 43.0-43.5C is reached within the tumor, and this temperature is maintained for 5-45 minutes. In cases of large size tumors it is preferable to reduce the blood flow in the tumor-feeding blood vessel after the administration thereto of the suspension.
U.S. Pat. No. 5,624,685 (Takahashi et al.) discloses a vascular lesion embolizing material comprising a high-polymer gel capable of absorbing water in an amount of 10 ml/g and more. When the high-polymer gel is supplied, either as such or after being bound with a binder or confined in a capsule, to the site of a blood vessel having a lesion to be repaired or its neighborhood, the gel swells upon contact with blood and spreads readily in the blood vessel to close the lumen of the blood vessels with lesion.
In accordance with the present invention there is provided a method of embolization. The method includes the use of a composition that contains biocompatible particles comprising a carbon surface, preferably provided in a biocompatible carrier. The particles can preferably be radiopaque, and can preferably be in the range from about 100 microns to 1,000 microns in transverse, cross-sectional dimension. The composition can be designed to be delivered into the body through a small-bore needle, cannula, or catheter.
The carbon of the surface may be, for example, pyrolytic carbon, e.g., isotropic carbon such as low temperature isotropic carbon, vitreous carbon, or any other useful form of carbon. The carbon can be coated onto a particle substrate as a thin coating or film, thereby creating a particle that has a highly biocompatible, carbon surface. While not required, pyrolytic carbon can be preferred.
The material of the particle substrate can be but is not necessarily biocompatible, and should be capable of withstanding the conditions of the coating process, which might include elevated temperatures. In particularly preferred embodiments, particle substrates can be radiopaque most preferably permanently radiopoque. Exemplary materials for radiopaque particle substrates can include metals and metal oxides such as zirconium oxide and aluminum oxide. Carbon itself, such as graphite or low temperature isotropic carbon, or other forms of carbon, may also be used as the particle substrate as well as other materials such as ceramics.
The fluid carrier can preferably be any biologically compatible material capable of delivering microparticles to a desired location, such as a biologically compatible suspension, solution, or other form of a fluid or gel. Specific examples of materials useful in biologically compatible carriers include saline, dextrans, glycerol, polyethylene glycol, and other polysaccharides or biocompatible polymers, either singly or in combination.
The use of the carbon-coated microparticles described herein has advantages over the use of other microparticles. Microparticles comprising a carbon coating, e.g., pyrolytic carbon, are very biocompatible. Preferred embodiments of the microparticle can be permanently radiopaque, e.g., by virtue of a radiopaque particle substrate. The location of the radiopaque particles can be monitored, by known methods, for as long as the radiopaque microparticles remain in a body. This is an improvement over many prior art contrastenhancing agents which biodegrade or otherwise lose their radiopacity over a period of days or weeks.
An aspect of the invention relates to a method for embolization including delivery of an embolic agent composition to a blood vessel to fill or plug the blood vessel and/or encourage clot formation so that blood flow through the vessel is reduced or stopped. The embolic agent composition contains microparticles having a carbon surface. The carbon can preferably be pyrolytic carbon. The microparticles can preferably contain a contrasting agent, and are most preferably radiopaque by virtue of a permanently radiopaque particle substrate.
Another aspect of the invention relates to a method for gynecological embolization. The method includes delivering an embolic agent composition to a blood vessel, the embolic agent composition including microparticles comprising a carbon surface. The carbon can preferably be pyrolytic carbon. The microparticles can preferably contain a contrasting agent, and are most preferably radiopaque by virtue of a permanently radiopaque particle substrate.
For purposes of the present disclosure, the following terms shall be given the following meanings.
The term xe2x80x9cbiocompatible,xe2x80x9d refers to materials which, in the amount employed, are non-toxic and substantially non-immunogenic when used internally in a patient, and which are substantially insoluble in blood. Suitable biocompatible materials include ceramics, metals such as titanium, gold, silver, stainless steel, metal oxides, carbon such as pyrolytic carbon or ultra low temperature isotropic carbon, etc.
The term xe2x80x9ccontrast-enhancingxe2x80x9d refers to materials capable of being monitored during injection into a mammalian subject by methods for monitoring and detecting such materials, for example by radiography or fluoroscopy. An example of a contrast-enhancing agent is a radiopaque material. Contrast-enhancing agents including radiopaque materials may be either water soluble or water insoluble. Examples of water soluble radiopaque materials include metrizamide, iopamidol, iothalamate sodium, iodomide sodium, and meglumine. Examples of water insoluble radiopaque materials include metals and metal oxides such as gold, titanium, silver, stainless steel, oxides thereof, aluminum oxide, zirconium oxide, etc.